tbuckley/cabot-search huggingface dataset:
Abstract 11470: Functional Validation of the Novel Role of SMARCB1 in Myocardial Fibrosis
Authors: Min Wang, Mahsima Shabani, Duan Liu, Jyotan Sahni, Hazley J Pyfferoen, Joao A Ac Lima, Naveen L Pereira
Journal: Circulation (2022)

Introduction: It has been previously demonstrated that cardiomyopathy predisposing common genetic variation in SMARCB1 is associated with interstitial myocardial fibrosis (MF) as determined by cardiac MRI (CMR) linking the development of cardiomyopathy with MF. SMARCB1 is known to be a tumor suppressor, but it’s role in the pathophysiology of MF and fibroblast physiology has not been functionally validated. Hypothesis: SMARCB1 plays an important role in regulating human cardiac fibroblast (HCF) differentiation/activation and collagen deposition, which are the critical steps in the development of MF. Methods: Cultured HCFs were treated with TGF-β1 (10ng/ml) for 48hrs to transdifferentiate into myofibroblasts, which are characterized by increased expression of α-smooth muscle actin (α-SMA, ACTA2) and collagen I (COL1A1). HCFs were transfected by siRNA using Lipofectamine™ RNAiMAX Transfection Reagent to knock-down (KD) the expression of SMARCB1 . Total RNA and protein were extracted from cell lysate followed by qPCR and Western blot (WB) to quantify the expression level of SMARCB1, ACTA2 and COL1A1. Triplicate experiments were performed using biologically independent samples. For statistical analysis, a paired two-tail t-test was used. Results: HCFs treatment with TGF-β1, resulted in a significant decrease in expression of SMARCB1 (p=0.031) with accompanying significant increase in expression of ACTA2 (p=0.025) and COL1A1 (p=0.0015) as compared to control by qPCR and WB. SMARCB1 KD resulted in a further significant increase in expression of ACTA2 (p=0.018) and COL1A1 (p=0.028) as compared to non-target siRNA control group at both the transcript and protein level. Conclusion: We demonstrate for the first time that a gene associated with the development of cardiomyopathy SMARCB1 mediates TGF-β1 induced cardiac fibrosis. These findings suggest SMARCB1 as a potential therapeutic target to attenuate MF in cardiomyopathy.
Abstract 11986: In-Hospital Outcomes in Patients With Peripheral Artery Disease Hospitalized for Acute Myocardial Infarction: From the NCDR Chest Pain Mi Registry
Authors: Kamil F Faridi, Shuang Li, Tracy Y Wang, Carlos Mena-Hurtado, Kim G Smolderen, Jennifer A Rymer, Jeptha P Curtis, Eric A Secemsky
Journal: Circulation (2022)

Introduction: Patients with peripheral artery disease (PAD) are at high risk for adverse cardiovascular events, including acute myocardial infarction (AMI). Though AMI care has improved, in-hospital outcomes for patients experiencing an AMI with comorbid PAD are not well described in recent practice. We hypothesized that patients with PAD would have higher rates of bleeding and mortality during AMI hospitalization. Methods: We assessed clinical characteristics and in-hospital major bleeding and mortality rates of patients admitted with AMI and comorbid PAD at 646 hospitals in the NCDR Chest Pain MI Registry from 1/2019 to 9/2021. Major bleeding and mortality were compared for patients with vs. without PAD using multivariable logistic regression. Results: Compared with patients admitted for AMI without PAD (n = 307,550), those with PAD (n = 24,585) were older, had more comorbidities including tobacco use, diabetes, prior AMI and heart failure, and more frequently presented with NSTEMI vs. STEMI. Patients with PAD had higher crude rates of in-hospital major bleeding (9.7% vs. 6.3%) and mortality (8.1% vs. 4.7%); in exploratory analyses, rates of other adverse in-hospital events were also higher ( Figure ). After multivariable adjustment, PAD was associated with an increased risk of major bleeding (adjusted OR [aOR] 1.23 [95% CI 1.17-1.30]). PAD was also associated with greater risk of in-hospital mortality (aOR 1.28 [95% CI 1.21-1.37]), particularly among patients over age 65 (aOR 1.32 [95% CI 1.23-1.42] for ≥65 years vs. 1.06 [95% CI 0.96-1.18] for patients &lt;65 years; interaction p = 0.02). Conclusions: Among patients hospitalized with AMI, those with PAD have greater comorbidity burden and increased risk of major bleeding. Patients with PAD, particularly those who are ≥65 years, also have increased risk of in-hospital death. These findings highlight a need for improved preventive efforts, tailored care pathways, and greater focus on AMI management in PAD patients.
Abstract 12474: Left Atrial Function and Clinical Outcomes After Tricuspid Valve Surgery for Atrial Functional Tricuspid Regurgitation
Authors: Kyu Kim, Kyu-Yong Ko, Iksung Cho, Geu-Ru Hong, Jong-Won Ha, Chi Y Shim
Journal: Circulation (2022)

Background: Atrial functional tricuspid regurgitation (AF-TR) caused by long-standing persistent atrial fibrillation is a common type of functional tricuspid regurgitation (TR). However, the data of functional changes and prognostic factor for clinical outcome after surgical correction are limited. Methods: Among 1,670 patients who underwent tricuspid valve (TV) surgery between January 2000 and December 2020, we included 83 AF-TR patients who had severe TR without any detectable cause other than chronic atrial fibrillation. We analyzed the changes of echocardiographic parameters at baseline, immediate postoperative period, and 6-month from TV surgery. In terms of left atrial (LA) function, LA emptying fraction (LAEF), LA reservoir strain, and LA stiffness index (the ratio of E/e’ and LAEF) were assessed. The primary outcome was composite of all-cause death or heart failure (HF) hospitalization. Results: The mean age was 69.1±9.2 years and women (60.2%) were more dominant. Right ventricular (RV) fractional area changes and RV-pulmonary artery coupling index were deteriorated postoperatively, but improved after 6-month. However, the postoperative changes of LAEF, LA reservoir strain, and LA stiffness index were consistent after 6 months from TV surgery. During median follow-up of 39.9 months, the primary outcome occurred in 20 (24.1%) patients. The patients with low baseline LAEF (&lt;16.7%) had significantly higher all-cause death or HF hospitalization incidence (log rank P&lt;0.001). In Cox multivariable regression analysis, LAEF was an independent predictor for primary outcome[p1] [KK2] (adjusted hazard ratio 9.51, 95% confidence interval 2.80-36.3; P&lt;0.001). Conclusion: In patients with AF-TR, preoperatively assessed LAEF was an independent predictor of clinical outcome after TV surgery.
Abstract 11182: The Morphological Feature of Left Atrial Appendage With Thrombus in Patients With Atrial Fibrillation
Authors: Miho Sugitani, Takanao Mine, Takehiro Kogame, Ryo Kitagaki, Eiji Fukuhara, Masaharu Ishihara
Journal: Circulation (2022)

Background: In atrial fibrillation (AF) patients, non-chicken wing type left atrial appendage (LAA) morphology is involved in thromboembolic events, and windsock and cauliﬂower LAA morphologies have been reported to be related to silent cerebral ischemia (CI). However, the morphology of the LAA in patients with left atrial appendage thrombus (LAAT) that is the main pathogenesis of cardiogenic CI due to AF remains unclear. Methods: We retrospectively studied the LAA morphology in 43 patients with LAAT detected by transesophageal echocardiography (TEE) prior to cardioversion or catheter ablation for AF and the LAA morphology of 144 patients without LAAT who undertook TEE on the same day, out of 1864 examined patients. Patients with significant valvular disease and cardiac surgery were excluded. LAA morphology constructed by computed tomography has been classiﬁed into 4 types: chicken wing, cauliﬂower, windsock, and cactus. We evaluated clinical data, blood samples, and transthoracic echocardiography at the time of TEE. Results: Non-paroxysmal AF (37% vs. 0%, P&lt;0.0001), higher history of heart failure (40% vs. 15%, P=0.0004), elevated BNP level (454±436 vs. 119±133 pg/mL, &lt;0.0001), reduced left ventricular ejection fraction (LVEF, 52.3±16.8% vs. 65.2±10.2%, P &lt;0.0001), larger LA dimension (LAD, 48.6±6.0 vs. 41.9±6.1 mL/m 2 , P&lt;0.0001), higher E/e` ratio (13.4±7.0 vs. 10.7±3.8, p=0.0017), and LAA morphology were associated with LAAT (Figure). On multivariate analysis, non-paroxysmal AF (P=0.0002), BNP level (P=0.0033), LVEF (P=0.0015), and LAA morphology (especially, cactus type LAA, P=0.0027) were significantly correlated to LAAT. Conclusion: The LAA morphology relates to the LAAT in AF patients. The characteristics of the LAA morphology in LAAT patients may be different from those in silent CI patients.
Abstract 12558: Social Determinants of Health and 90-day Readmissions Among Pediatric Patients With Cardiac Disease
Authors: Miriam T Fox, Patrice Melvin, Faraz Alizadeh, Jessica A Barreto, Ravi R Thiagarajan, Valerie Ward, Katie Moynihan
Journal: Circulation (2022)

Introduction: Social determinants of health (SDoH) impact general pediatric readmissions and pediatric cardiac surgical mortality. Yet, little is known of their influence on readmissions in pediatric cardiac disease. Hypothesis: Children with cardiac disease from underrepresented populations, under-resourced neighborhoods or on public insurance are more likely to experience readmission. Methods: This was a multicenter retrospective study of patients &lt;18 years with a cardiac diagnosis and index hospitalization with survival to discharge in the Pediatric Health Information System database (1/1/2017-12/31/2020). The outcome was 90-day all-cause non-elective readmission. SDoH examined were race/ethnicity, insurance type, income, and child opportunity index (COI; a composite variable of residential socioeconomic resources). Mixed effects multivariable logistic regression models were performed. Results: Of 249,222 cardiac-related admissions in 161,039 patients, 90-day readmissions were 55,770 (22.4%). Overall mortality was 2.8% (1.8% in readmissions). Clinical factors associated with readmission were infancy, non-surgical index admission, extracorporeal membrane oxygenation, greater length of stay, and non-cardiac comorbidities. Controlling for these factors, there was greater adjusted odds of 90-day readmission in patients with public or other insurance (vs private), Hispanic or Non-Hispanic Black race/ethnicity (vs Non-Hispanic White) and lower COI area residents (vs higher) [Table]. Sub-analysis in the 38,711 cardiac surgical admissions (15.8% 90-day readmission rate), found similar observations for race and insurance in adjusted analyses. Conclusions: Children with cardiac disease from under-resourced areas, underrepresented populations and/or on public insurance have higher odds of 90-day readmission. Our data provide insights for future interventions to optimize hospital discharge planning in this population.
Abstract 12291: Natriuretic Peptide Levels and Predicting Risk of Developing New Diabetes Mellitus or Metabolic Syndrome: A Population Based Study
Authors: Jasraj S Marjara, Fadi W Adel, Christopher Scott, Horng Chen
Journal: Circulation (2022)

Introduction: The prevalence of metabolic syndrome (MS), and diabetes mellitus (DM) is increasing, and the use of biomarkers to identify subjects at risk of developing MS or DM may be useful for disease prevention. Natriuretic peptides (NPs) are well known for their role as biomarkers in heart failure (HF), but are increasingly being recognized for their favorable metabolic actions and potential role as risk modifiers for the development of DM and MS. To date, however, this risk relationship has not been well defined in the general population. Hypothesis: Adults in the general population with lower NP levels are at higher risk for developing DM or MS. Methods: A retrospective review of the Olmsted County Heart Function Study cohort, a population-based random sample of 2042 Olmsted County, MN residents aged ≥ 45 years. A subgroup of community-dwelling subjects without MS or DM at Visit 1 was identified and subjects returned for followup after 4 years (Visit 2). We compared the characteristics of subjects that developed MS or DM after 4 years to those that did not. Results: Of the 911 subjects who did not have MS or DM at visit 1, 93 (10.2%) developed either MS or DM at visit 2. Subjects who developed MS or DM at visit 2 were more likely to have higher baseline BMI (p &lt;0.001), lower HDL (p&lt;0.001), higher triglycerides (p &lt; 0.001), higher insulin (p&lt; 0.001), higher aldosterone (p &lt; 0.001) levels, lower NT-proANP (p&lt;0.001) and lower NT-proBNP levels (p &lt; 0.01) compared to those that did not develop MS or DM. Those that developed MS or DM were also at higher risk for development of HF when controlling for age and sex (HR 2.73 CI 1.25-5.96). On univariate analysis, higher baseline levels of NT-proANP and NT pro-BNP had a significant negative association with developing new MS or DM (ORs per 1 SD increase: 0.64, CI 0.51-0.79 p &lt; 0.0001 and 0.76, CI 0.62-0.95 p=0.016, respectively). Conclusions: Among adults aged ≥ 45 years in the community, low levels of NT- ANP and NT-proBNP are associated with increased risk of development of DM and MS. Further studies are warranted to determine if potentiating the natriuretic peptide system would delay the development of DM or MS.
Abstract 11298: Bioenergetics-Independent Stress Response to Mitochondrial Protein Import Clogging in the Heart
Authors: Gargi Mishra, Arnav Rana, Liam Coyne, Xiaowen Wang, Xin Jie Chen
Journal: Circulation (2022)

Mitochondria are double-membraned organelles indispensable in metabolically active organs such as the heart. Much of the mitochondrial proteome is encoded by the nuclear genome and requires import into mitochondria via channels present on the outer and inner mitochondrial membranes. If protein import goes awry at any step, it can cause unimported mitochondrial proteins to accumulate in the cytosol, leading to mitochondrial Precursor Overaccumulation Stress (mPOS). Defects in mitochondrial protein import have been linked to many forms of heart disease such as Senger’s syndrome, cardiac arrhythmia, and chronic atrial fibrillation. The A123D mutation in adenine nucleotide translocase 1 (Ant1), an ATP/ADP antiporter present on the mitochondrial inner membrane, has been shown to cause hypertrophic cardiomyopathy, while other mutations in Ant1 (A114P, A90D, V289M, L98P) have been shown to cause Autosomal Dominant Progressive External Ophthalmoplegia. Our studies suggested that the mutant ANT1 can cause mitochondrial protein import clogging. To characterize the pathophysiology induced by mitochondrial protein import clogging, we developed a mouse model (the “clogger mouse”) expressing two clinically relevant mutations in Ant1 , namely A114P and A123D . While prior work on this model revealed a low-penetrant neurodegenerative and mild myopathic phenotype, the impact of this mutation on the heart has not been studied. In the current study, we show that expression of Ant1 A114P, A123D has little effect on mitochondrial respiration and heart function. This is consistent with the rapid degradation of Ant1 A114P, A123D in the heart. Interestingly, transcriptomic analysis revealed an altered expression of circadian regulator and output genes such as Clock, Ciart, Per1-3, Cebpb and Hlf in the clogger mouse relative to wild type. These data suggest that mitochondrial protein import clogging can induce a stress response independent of bioenergetics. It also led us to hypothesize that the circadian pathway plays a role in adapting to mitochondria-induced proteostatic stress in the heart. Our current experiments focused on testing this hypothesis are anticipated to help us understand how the heart can uniquely adapt to mitochondrial protein import clogging.
Abstract 12150: Acute Type B Aortic Dissection a 15-Year, Single-Center Experience
Authors: Derek R Serna-Gallegos, Yancheng Dai, James Brown, Edgar Aranda-Michel, Valentino Bianco, Sarah Yousef, Ibrahim Sultan
Journal: Circulation (2022)

Introduction: Treatment of acute type B aortic dissection (ATBAD) has evolved with the use of endovascular technology. This study evaluates the short and long-term outcomes of patients with ATBAD over a 15-year period. Methods: A retrospective review identified patients with ATBAD at our institution between 2006 and 2020. Patients were analyzed based on presentation status (complicated vs. uncomplicated) and treatment. Complicated ATBAD (cATBAD) included malperfusion of any vascular bed, intractable pain, rupture, or rapid expansion. Postoperative outcomes were evaluated within the initial 30 days after diagnosis when managed medically or within thirty days of surgical intervention. Descriptive statistics was performed to assess short-term outcomes. Kaplan-Meier survival was performed to assess long-term mortality. Results: A total of 296 patients presented with ATBAD in the study period. Out of those, 121 patients presented with cATBAD, while 175 patients presented with uncomplicated ATBAD (uATBAD). Out of the cATBAD group, 89 were treated with TEVAR, and 32 were treated with medication only. The cATBAD group was younger than the uCTBAD group (62.0 vs. 65.2, p=0.05). Early mortality was more common in cATBAD than uATBAD (9.9% vs 2.3%, p=0.013). When comparing cATBAD who underwent TEVAR vs conservative medical management, early mortality was higher in the medication only group (12.5% vs 9.0% p = 0.013). Permanent paraplegia occurred in 1.1% (1/89)of patients undergoing TEVAR. Kaplan-Meier survival analysis demonstrated no significant difference in long-term mortality between the cATBAD and uATBAD groups (Logrank p = 0.23). Among the uATBAD patients, 10.3% (18/175) required future intervention for type B dissection (12 TEVAR, 6 open). Among the TEVAR patients, 20.2% (18/89) required re-operations (11 endovascular repairs, 7 open). Conclusions: ATBAD is associated with significant morbidity and mortality, especially in the setting of a complicated presentation. While uATBAD is associated with better short-term outcomes, the diminishing difference in long-term outcome between cATBAD and uATBAD calls for reevaluation of our indications for intervention and may suggest that the remodeling associated with TEVAR could have long term benefit.
Abstract 11603: Comparing Analytical Methods for Composite Endpoints in Heart Failure With Reduced Ejection Fraction: Insights From the VICTORIA Trial
Authors: Cynthia M Westerhout, Sarah Rathwell, Kevin J Anstrom, Adrian F Hernandez, Piotr Ponikowski, Justin A Ezekowitz, Adriaan A Voors, Michael Felker, Jeffrey Bakal, Robert O Blaustein, Richard Nkulikiyinka, Christopher M OConnor, Paul W Armstrong
Journal: Circulation (2022)

Background: In the VICTORIA trial in patients with heart failure with reduced ejection fraction, vericiguat (V) versus placebo (P) reduced the primary composite outcome (heart failure hospitalization [HFH] or cardiovascular death [CVD]) from 38.5 to 35.5% (1869 events: V=897, P=972) ( Fig A ). In this prespecified analysis, we assessed vericiguat’s treatment effect using weighted composite endpoint (WCEP) and win-ratio (WR) methods. Methods: Clinical events were centrally adjudicated. A survey of 37 international trial leaders conducted before database lock led to the derivation of relative weights of subtypes of HFH (mild [change in therapy] 0.39; moderate [requiring IV diuresis] 0.50; severe [urgent deterioration requiring inotropic support] 0.67) and CVD (1.0). A WCEP model estimated the effect of vericiguat on mean survival after severity-weighting recurrent HFH events and CVD. The unmatched WR approach, which accounted for recurrent HFH events, was applied with the hierarchy of HFH&lt;CVD. Results: All 3412 primary clinical events in 5050 patients were analyzed in the WCEP model (855 CVD [V=414, P=441]; 875 severe HFH [V=416, P=459]; 1614 moderate HFH [V=767, P=847]; 68 mild HFH [V=38, P=30]). WCEP yielded a higher hospitalization-adjusted survival in the vericiguat arm (mean 78.2 vs 75.6%; difference [95% CI]: 2.4% (1.7-3.2%]; p&lt;.0001) ( Fig B ). 2608 events were used in the WR model (V=1232, P=1376) which also found an improvement in clinical outcomes in the vericiguat arm (WR [95% CI]: 1.13 [1.03-1.24]; p=0.01) ( Fig C ). Conclusions: These 2 alternative methods complement the primary VICTORIA analysis with more refined characterization of vericiguat’s treatment effect. While both WCEP and WR included recurrent events, the prespecified WCEP approach allowed for inclusion of all recurrent events and further insight into the severity of HFH. These findings may help inform health providers, consumers, and those planning future HFrEF trials.
Abstract 11825: Reduction in Muscle Mass in the Left Atrial Wall is Associated With Atrial Fibrillation
Authors: Satoshi Matsushita, TAIRA YAMAMOTO, Daisuke Endo, Hirotaka Inaba, Kazuo Minematsu, Yokoyama Norihiko, Shoji Yayoi, Asai Tohru, Amano Atsushi, Tabata Minoru
Journal: Circulation (2022)

Introduction The left atrium (LA) plays a central role in the occurrence of atrial fibrillation (AF). Although many studies have demonstrated that the dilatation or alteration of the wall thickness of the LA, so called LA remodeling, was strongly associated with AF, the detailed mechanism is still unclear. Materials and Methods We retrospectively analyzed all samples of LA wall obtained during cardiac surgery in Juntendo University Hospital from 2014 to 2020. The samples were processed with Masson’s trichrome staining, then layer analysis was performed. The histological data was compared with the clinical background. Results A total of 60 patients’ samples were analyzed. The thickness of the LA wall was 1257 to 6905 μm. Layer analysis of the LA wall demonstrated that the wall thickness was not associated with the volume (R 2 = 0.0287, p = 0.098). Multiple regression analysis determined that the only factor associated with thinning of the LA was the existence of AF (p &lt;0.05). Moreover, LA wall thickness was well correlated with muscle layer thickness (R 2 = 0.744, p &lt;0.001). In addition, the patients who had AF for one year or more showed significant reduction in muscle mass compared to those with AF for less than one year (18.6% vs. 24.3%, p &lt;0.05). Among 36 patients who underwent concomitant Maze procedure during surgery, 9 had recurrent AF at 1 year after surgery. Age (p &lt;0.05), duration of AF (p &lt;0.01), and muscle area (p &lt;0.01) were detected as risk factors for recurrence. Conclusion AF was detected as the only factor associated with a reduction in the cardiac muscle mass in the LA wall. Chronic AF of more than one year’s duration enhanced the risk of reduction in the LA muscle mass. Furthermore, the reduction of the muscle mass was a comorbid factor for the recurrence of AF after the Maze procedure, along with age and duration of AF. Our results indicate that the muscle mass may be a novel predictor indicating the need for the Maze procedure.